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Stewart: Improving Drug Therapy for Children with Brain Tumors

The focus of my laboratory research is to improve drug therapy for children with primary CNS tumors by better understanding the systemic and CNS disposition of drugs used to treat these tumors. To characterize and understand anti-cancer drug CNS penetration, we use relevant, tumor specific mouse models of pediatric brain tumors and cerebral microdialysis sampling, sensitive bioanalytical methods (LC MS/MS), and pharmacokinetic modeling to develop a better understanding of the relation between CNS drug disposition and antitumor effect. Using these preclinical data, we can translate the findings to the clinic with the ultimate goal of improving therapy for children with brain tumors.

Another focus of the lab is to learn more about the disposition of anti-cancer agents in infants and young children less than 3 years of age, since this population is not well understood, and often experience an increased risk of morbidity, poor tumor control, and increased incidence of late effects after anticancer drug treatment. The paucity of data is particularly relevant in children with malignant brain tumors where intensive chemotherapy has been substituted for, or used to delay craniospinal irradiation. However, investigators often lack crucial pharmacokinetic (PK) and drug effect data (e.g., toxicity or antitumor response) necessary when designing drug regimens for these clinical trials; thus, they are forced to rely upon dosing regimens that have largely been derived by scaling down adult dosages based solely upon toxicity.

For these studies, we are developing both population and physiologically-based pharmacokinetic (PBPK) models of drugs used to treat infants and young children with brain tumors. Population PK models will describe inter-individual and inter-occasion variability in drug disposition associated with physiological changes and genetic polymorphisms (DMET array). PBPK modeling will further account for physiological characteristics specific to our patient population and the physiochemical characteristics specific to each drug studied that affect the PK of these drugs and metabolites. We are also using both statistical and mechanistic models to identify pharmacodynamic (PD) and PK-PD response relationships for anti-cancer drugs in infants and young children. The results identified from pharmacokinetic, PK-PD, and PBPK modeling will be integrated into dosing regimens that account for developmental pharmacology and achieve pharmacologic goals and enable us to achieve more uniform systemic exposure to anticancer drugs across all pediatric age groups.

Collectively, these studies narrow the gap in our understanding of the clinical pharmacology of anti-cancer agents used to treat infants and young children. Our long-term goal is to determine rational dosing regimens for infants and young children by better understanding the developmental pharmacology of anti-cancer drugs and to apply these regimens to therapy for other childhood malignancies and chronic medical conditions.